Prevention of cisplatin‐induced hearing loss in children: Informing the design of future clinical trials

Abstract

Cisplatin is an essential chemotherapeutic agent in the treatment of many pediatric cancers. Unfortunately, cisplatin‐induced hearing loss (CIHL) is a common, clinically significant side effect with life‐long ramifications, particularly for young children. ACCL05C1 and ACCL0431 are two recently completed Children’s Oncology Group studies focused on the measurement and prevention of CIHL. The purpose of this paper was to gain insights from ACCL05C1 and ACCL0431, the first published cooperative group studies dedicated solely to CIHL, to inform the design of future pediatric otoprotection trials. Use of otoprotective agents is an attractive strategy for preventing CIHL, but their successful development must overcome a unique constellation of methodological challenges related to translating preclinical research into clinical trials that are feasible, evaluate practical interventions, and limit risk. Issues particularly important for children include use of appropriate methods for hearing assessment and CIHL severity grading, and use of trial designs that are well‐informed by preclinical models and suitable for relatively small sample sizes. Increasing interest has made available new funding opportunities for expanding this urgently needed research.

Advances and challenges in adeno-associated viral inner-ear gene therapy for sensorineural hearing loss

“…IHC and OHC are the most studied target in genetic or environmental acquired diseases like Usher syndrome (USH)III, TMC1 (transmembrane channel-like 1) mutation, VGLUT3 (glutamate transporter-3 vesicular) mutation, noise-induced HL (NIHL), and ototoxicity due to drugs (like cisplatin, aminoglycosides, and others). 74 , 75 , 76 , 77 , 78 , 79 These auditory signals are transmitted to the brain via spiral ganglion neuron (SGN), with type I SGNs (90% of the total SGN population) connecting to IHCs and type II SGNs (5%–10%) connecting to OHCs. Brain-derived neurotrophic factors (BDNF) and neurotrophin-3 (NT-3) are expressed in HCs and SCs in the developing organ of Corti and are essential for normal function of SGNs.…”

Pediatric Ototoxicity: Current Trends and Management

“…Cancer therapy protocols advise the oncologist to consider reducing the dose of (or eliminating) of an ototoxic chemotherapy if a patient is documented to have increasingly severe adverse events (such as having a Grade 3 hearing loss). 11 Reduction in chemotherapy may jeopardize treatment efficacy; that is, the oncologist risks the child's life to lessen the risk for hearing loss from chemotherapy.…”

Assessment of provider perspectives on otoprotection research for children and adolescents: A Children's Oncology Group Cancer Control and Supportive Care Committee survey

“…In contrast, ACCL0431 enrolled a heterogeneous mix of patients with multiple cancer types and stages receiving various cisplatin regimens; in a post hoc stratified survival analysis by extent of disease, lower EFS and OS were found in those receiving STS and classified as having disseminated disease, but not in those with localized disease. Definitive interpretation of these combined results has proven challenging due to key design differences between the two studies 14 . Consequently, the results of ACCL0431 and SIOPEL‐6 are considered complementary and have been used in combination to inform thoughtful discussion regarding the efficacy, safety, and role of STS in pediatric cancer care and in otoprotection research 13,15‐18 .…”